Sabine Heiland

Hemostatic Therapy in Experimental Intracerebral Hemorrhage Associated With the Direct Thrombin Inhibitor Dabigatran

Background and Purpose— Dabigatran-etexilate (DE) recently has been approved for stroke prevention in atrial fibrillation. However, lack of effective antagonists represents a major concern in the event of intracerebral hemorrhage (ICH). The aims of the present study were to establish a murine model of ICH associated with dabigatran, and to test the efficacy of different hemostatic factors in preventing hematoma growth. Methods— In C57BL/6 mice receiving DE (4.5 or 9.0 mg/kg), in vivo and in vitro coagulation assays and dabigatran plasma levels were measured repeatedly. Thirty minutes after inducing ICH by striatal collagenase injection, mice received an intravenous injection of saline, prothrombin complex concentrate (PCC; 100 U/kg), murine fresh-frozen plasma (200 &mgr;L), or recombinant human factor VIIa (8.0 mg/kg). ICH volume was quantified on brain cryosections 24 hours later. Results— DE substantially prolonged tail vein bleeding time and ecarin clotting time for 4 hours corresponding to dabigatran plasma levels. Intracerebral hematoma expansion was observed mainly during the first 3 hours on serial T2* MRI. Anticoagulation with high doses of DE increased the hematoma volume significantly. PCC and, less consistently, fresh-frozen plasma prevented excess hematoma expansion caused by DE, whereas recombinant human factor VIIa was ineffective. Prevention of hematoma growth and reversal of tail vein bleeding time by PCC were dose-dependent. Conclusions— The study provides strong evidence that PCC and, less consistently, fresh-frozen plasma prevent excess intracerebral hematoma expansion in a murine ICH model associated with dabigatran. The efficacy and safety of this strategy must be further evaluated in clinical studies.

Comparison of Perfusion Computed Tomography and Computed Tomography Angiography Source Images With Perfusion-Weighted Imaging and Diffusion-Weighted Imaging in Patients With Acute Stroke of Less Than 6 Hours’ Duration

Background and Purpose— We aimed to determine the diagnostic value of perfusion computed tomography (PCT) and CT angiography (CTA) including CTA source images (CTA-SI) in comparison with perfusion-weighted magnetic resonance imaging (MRI) (PWI) and diffusion-weighted MRI (DWI) in acute stroke <6 hours. Methods— Noncontrast-enhanced CT, PCT, CTA, stroke MRI, including PWI and DWI, and MR angiography (MRA), were performed in patients with symptoms of acute stroke lasting <6 hours. We analyzed ischemic lesion volumes on patients’ arrival as shown on NECT, PCT, CTA-SI, DWI, and PWI (Wilcoxon, Spearman, Bland–Altman) and compared them to the infarct extent as shown on day 5 NECT. Results— Twenty-two stroke patients underwent CT and MRI scanning within 6 hours. PCT time to peak (PCT-TTP) volumes did not differ from PWI-TTP (P =0.686 for patients who did not undergo thrombolysis/ P =0.328 for patients who underwent thrombolysis), nor did PCT cerebral blood volume (PCT-CBV) differ from PWI-CBV (P =0.893/ P =0.169). CTA-SI volumes did not differ from DWI volumes (P =0.465/ P =0.086). Lesion volumes measured in PCT maps significantly correlated with lesion volumes on PWI (P =0.0047, r =1.0/ P =0.0019, r =0.897 for TTP; P =0.0054, r =0.983/ P =0.0026, r =0.871 for CBV). Also, PCT-CBV lesion volumes significantly correlated with follow-up CT lesion volumes (P =0.0047, r =1.0/ P =0.0046, r =0.819). Conclusions— In hyperacute stroke, the combination of PCT and CTA can render important diagnostic information regarding the infarct extent and the perfusion deficit. Lesions on PCT-TTP and PCT-CBV do not differ from lesions on PWI-TTP and PWI-CBV; lesions on CTA source images do not differ from lesions on DWI. The combination of noncontrast-enhanced CT (NECT), perfusion CT (PCT), and CT angiography (CTA) can render additional information within <15 minutes and may help in therapeutic decision-making if PWI and DWI are not available or cannot be performed on specific patients.

Gadolinium Retention in the Dentate Nucleus and Globus Pallidus Is Dependent on the Class of Contrast Agent

PURPOSE To compare changes in signal intensity (SI) ratios of the dentate nucleus (DN) and the globus pallidus (GP) to those of other structures on unenhanced T1-weighted magnetic resonance (MR) images between linear and macrocyclic gadolinium-based contrast agents (GBCAs). MATERIALS AND METHODS The study was approved by the ethical committee of the University of Heidelberg (reference no. S-324/2014). Owing to the retrospective character of the study, the ethical committee did not require any written informed consent. Two groups of 50 patients who underwent at least six consecutive MR imaging examinations with the exclusive use of either a linear GBCA (gadopentetate dimeglumine) or a macrocyclic GBCA (gadoterate meglumine) were analyzed retrospectively. The difference in mean SI ratios of DN to pons and GP to thalamus on unenhanced T1-weighted images from the last and first examinations was calculated. One-sample and independent-sample t tests were used to assess the difference in SI ratios for both groups, and regression analysis was performed to account for potential confounders. RESULTS The SI ratio difference in the linear group was greater than 0 (mean DN difference ± standard deviation, 0.0407 ± 0.0398 [P < .001]; GP, 0.0287 ± 0.0275 [P < .001]) and significantly larger (DN, P < .001 and standardized difference of 1.16; GP, P < .001 and standardized difference of 0.81) than that in the macrocyclic group, which did not differ from 0 (DN, 0.0016 ± 0.0266 [P = .680]; GP, 0.0031 ± 0.0354 [P = .538]). The SI ratio difference between the last and first examinations for the DN remained significantly different between the two groups in the regression analysis (P < .001). CONCLUSION This study indicates that an SI increase in the DN and GP on T1-weighted images is caused by serial application of the linear GBCA gadopentetate dimeglumine but not by the macrocyclic GBCA gadoterate meglumine. Clinical implications of this observation remain unclear.

Stroke magnetic resonance imaging within 6 hours after onset of hyperacute cerebral ischemia.

We studied the diagnostic and prognostic value of diffusion‐ and perfusion‐weighted magnetic resonancce imaging (DWI and PWI) for the initial evaluation and follow‐up monitoring of patients with stroke that had ensued less than 6 hours previously. Further, we examined the role of vessel patency or occlusion and subsequent recanalization or persistent occlusion for further clinical and morphological stroke progression so as to define categories of patients and facilitate treatment decisions. Fifty‐one patients underwent stroke magnetic resonance imaging (DWI, PWI, magnetic resonance angiography, and T2‐weighted imaging) within 3.3 ± 1.29 hours, and, of those, 41 underwent follow‐up magnetic resonance imaging on day 2 and 28 on day 5. In addition, we assessed clinical scores (on the National Institutes of Health Stroke Scale, Scandinavian Stroke Scale, Barthel Index, and Modified Rankin Scale) on days 1, 2, 5, 30, and 90 and performed volumetric analysis of lesion volumes. In all, 25 patients had a proximal, 18 a distal, and 8 no vessel occlusion. Furthermore, 15 of 43 patients exhibited recanalization on day 2. Vessel occlusion was associated with a PWI‐DWI mismatch on the initial magnetic resonance imaging, vessel patency with a PWI‐DWI match (p < 0.0001). Outcome scores and lesion volumes differed significantly between patients experiencing recanalization and those who did not (all p < 0.0001). Acute DWI and PWI lesion volumes correlated poorly with acute clinical scores and only modestly with outcome scores. We have concluded on the basis of this study that early recanalization saves tissue at risk of ischemic infarction and results in significantly smaller infarcts and a significantly better clinical outcome. Patients with proximal vessel occlusions have a larger amount of tissue at risk, a lower recanalization rate, and a worse outcome. Urgent recanalization seems to be of utmost importance for these patients. Ann Neurol 2001;49:460–469

Comparison of CT and CT Angiography Source Images With Diffusion-Weighted Imaging in Patients With Acute Stroke Within 6 Hours After Onset

Background and Purpose— Although stroke MRI has advantages over other diagnostic imaging modalities in acute stroke patients, most of these individuals are admitted to emergency units without MRI facilities. There is a need for an accurate diagnostic tool that rapidly and reliably detects hemorrhage, extent of ischemia, and vessel status and potentially estimates tissue at risk. We sought to determine the diagnostic accuracy of the combination of non–contrast-enhanced CT, CT angiography (CTA), and CTA source images (CTA-SI, showing early parenchymal contrast enhancement) in comparison with a multiparametric stroke MRI protocol in patients with acute stroke within 6 hours after onset. Methods— Non–contrast-enhanced CT, CTA, stroke MRI including diffusion-weighted imaging (DWI), and MR angiography (MRA) were performed in patients with symptoms of acute stroke within 6 hours after onset. We analyzed infarct volumes on days 1 and 5 as shown on CTA-SI, DWI, and T2-weighted images (Wilcoxon, Mann-Whitney, Spearman tests), estimated the collateral status, and assessed clinical outcome (modified Rankin Scale, Barthel Index, National Institutes of Health Stroke Scale, Scandinavian Stroke Scale). Results— We analyzed the data of 20 stroke patients who underwent CT and MRI scanning within 6 hours (mean, 2.83 and 3.38 hours, respectively). Vessel occlusion was present in 16 of 20 patients. CTA-SI volumes did not differ from DWI volumes (P =0.601). Furthermore, the CTA-SI lesion volumes significantly correlated with the initial DWI lesion volumes (P <0.0001, r =0.922) and with outcome lesion volumes (P =0.013 r =0.736). Patients with poor collaterals experienced infarct growth (P =0.0058) and had a significantly worse clinical outcome (all P <0.012); patients with good collaterals did not (P =0.176). Conclusions— The combination of non–contrast-enhanced CT (exclusion of intracranial hemorrhage), CTA (vessel status), and early contrast-enhanced CTA-SI (demarcation of irreversible infarct) allows diagnostic assessment of acute stroke with a quality comparable to that of stroke MRI. Furthermore, it is possible to distinguish patients at risk of infarct growth from those who are not according to the collateral status, in analogy with the stroke MRI mismatch concept.

Monitoring Intravenous Recombinant Tissue Plasminogen Activator Thrombolysis for Acute Ischemic Stroke With Diffusion and Perfusion MRI

BACKGROUND AND PURPOSE Intravenous recombinant tissue plasminogen activator (rtPA) administration is an effective therapy for ischemic stroke when initiated within 3 hours and possibly up to 6 hours after symptom onset. To improve patient selection, a fast diagnostic tool that allows reliable diagnosis of hemorrhage and ischemia, vessel status, and tissue at risk at an early stage may be useful. We studied the feasibility of stroke MRI for the initial evaluation and follow-up monitoring of patients undergoing intravenous thrombolysis. METHODS Stroke MRI (diffusion- and perfusion-weighted imaging [DWI and PWI, respectively], magnetic resonance angiography, and T2-weighted imaging) was performed before, during, or after thrombolysis and on days 2 and 5. We assessed clinical scores (National Institutes of Health Stroke Scale [NIHSS], Scandinavian Stroke Scale [SSS], Barthel Index, and Rankin scale) at days 1, 2, 5, 30, and 90. Furthermore, we performed volumetric analysis of infarct volumes on days 1, 2, and 5 as shown in PWI, DWI, and T2-weighted imaging. RESULTS Twenty-four patients received rtPA within a mean time interval after symptom onset of 3.27 hours and stroke MRI of 3.43 hours. Vessel occlusion was present in 20 of 24 patients; 11 vessels recanalized (group 1), and 9 did not (group 2). The baseline PWI lesion volume was significantly larger (P=0.008) than outcome lesion size in group 1, whereas baseline DWI lesion volume was significantly smaller (P=0.008) than final infarct size in group 2. Intergroup outcome differed significantly for all scores at days 30 and 90 (all P<0.01). Intragroup differences were significant in group 1 for change in SSS and NIHSS between day 1 and day 30 (P=0.003) and for SSS only between day 1 and day 90 (P=0.004). CONCLUSIONS Stroke MRI provides comprehensive prognostically relevant information regarding the brain in hyperacute stroke. Stroke MRI may be used as a single imaging tool in acute stroke to identify and monitor candidates for thrombolysis. It is proposed that stroke MRI is safe, reliable, and cost effective; however, our data do not prove this assumption. Early recanalization achieved by thrombolysis can save tissue at risk if present and may result in significantly smaller infarcts and a significantly better outcome.

Distinguishing of primary cerebral lymphoma from high-grade glioma with perfusion-weighted magnetic resonance imaging

To assess the usefulness of perfusion-weighted echo-planar magnetic resonance imaging in the differential diagnosis of primary supratentorial lymphoma (PCNSL) and glioblastoma (GBM), 12 patients with a PCNSL and 12 with a GBM were examined using a 1.5 T magnetic resonance (MR) imager. With dynamic-susceptibility contrast MR imaging the intensity-time curves of each tumor were analyzed, and we determined the relative regional cerebral blood volume ratios (rrCBV [tumor/contralateral white matter (WM)]) to find out whether these parameters could be used to separate PCNSL from GBM. The maximum rrCBV ratio in the PCNSL was significantly lower than that of the GBM (P<0.0001). Comparing the intensity-time curves for the two tumor groups, the PCNSL showed a characteristic type of curve with a significant increase in signal intensity above the baseline due to massive leakage of contrast media into the interstitial space. PCNSL tend to have low maximum CBV ratios and typical intensity-time curves. These two parameters may be useful in distinguishing PCNSL from GBM.

Decompressive Craniectomy for Cerebral Infarction An Experimental Study in Rats

BACKGROUND AND PURPOSE Acute ischemia in the territory of the carotid artery can lead to massive cerebral edema with raised intracranial pressure and progression to coma and death due to uncal, cingulate, or tonsillar herniation. Thus far, only anecdotal experience with supratentorial ischemia treated by decompressive craniectomy has been reported; and there are no published experimental data dealing with this kind of therapy in acute supratentorial stroke. In this study, we present our results on the effect of decompressive craniectomy in an endovascular model of cerebral infarction in rats. METHODS Focal cerebral ischemia was induced in 50 rats using an endovascular occlusion technique of the middle cerebral artery. Decompressive craniectomy was performed in 30 animals: in 15 animals after 1 hour and in the remaining 15 animals 24 hours after vessel occlusion. Twenty animals were not treated by decompressive craniectomy (control group). RESULTS Mortality in the nontreated group was 35%, whereas none of the animals treated by decompressive craniectomy died. Neurological behavior, weight loss, and infarction size were all significantly better in the animals treated by decompressive craniectomy, regardless of whether they had been treated after 1 or 24 hours (P < .01). CONCLUSIONS Our results suggest that decompressive craniectomy for cerebral ischemia not only reduces mortality but also significantly improves outcome and reduces infarction size, probably because of increased perfusion pressure through leptomeningeal collaterals. This experimental study suggests that a controlled study of decompressive craniectomy in patients with acute internal carotid or middle cerebral artery occlusion would be worthwhile. By performing decompressive craniectomy in a small, selected group of patients, neurosurgeons may play an important role in the management of these patients.

Trimodal Cancer Treatment: Beneficial Effects of Combined Antiangiogenesis, Radiation, and Chemotherapy

It has been suggested that chemotherapy and radiotherapy could favorably be combined with antiangiogenesis in dual anticancer strategy combinations. Here we investigate the effects of a trimodal strategy consisting of all three therapy approaches administered concurrently. We found that in vitro and in vivo, the antiendothelial and antitumor effects of the triple therapy combination consisting of SU11657 (a multitargeted small molecule inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor tyrosine kinases), Pemetrexed (a multitargeted folate antimetabolite), and ionizing radiation were superior to all single and dual combinations. The superior effects in human umbilical vein endothelial cells and tumor cells (A431) were evident in cell proliferation, migration, tube formation, clonogenic survival, and apoptosis assays (sub-G1 and caspase-3 assessment). Exploring potential effects on cell survival signaling, we found that radiation and chemotherapy induced endothelial cell Akt phosphorylation, but SU11657 could attenuate this process in vitro and in vivo in A431 human tumor xenografts growing s.c. on BALB/c nu/nu mice. Triple therapy further decreased tumor cell proliferation (Ki-67 index) and vessel count (CD31 staining), and induced greater tumor growth delay versus all other therapy regimens without increasing apparent toxicity. When testing different treatment schedules for the A431 tumor, we found that the regimen with radiotherapy (7.5 Gy single dose), given after the institution of SU11657 treatment, was more effective than radiotherapy preceding SU11657 treatment. Accordingly, we found that SU11657 markedly reduced intratumoral interstitial fluid pressure from 8.8 +/- 2.6 to 4.2 +/- 1.5 mm Hg after 1 day. Likewise, quantitative T2-weighed magnetic resonance imaging measurements showed that SU11657-treated mice had reduced intratumoral edema. Our data indicates that inhibition of Akt signaling by antiangiogenic treatment with SU11657 may result in: (a) normalization of tumor blood vessels that cause prerequisite physiologic conditions for subsequent radio/chemotherapy, and (b) direct resensitization of endothelial cells to radio/chemotherapy. We conclude that trimodal cancer therapy combining antiangiogenesis, chemotherapy, and radiotherapy has beneficial molecular and physiologic effects to emerge as a clinically relevant antitumor strategy.

Brain tumour cells interconnect to a functional and resistant network

Astrocytic brain tumours, including glioblastomas, are incurable neoplasms characterized by diffusely infiltrative growth. Here we show that many tumour cells in astrocytomas extend ultra-long membrane protrusions, and use these distinct tumour microtubes as routes for brain invasion, proliferation, and to interconnect over long distances. The resulting network allows multicellular communication through microtube-associated gap junctions. When damage to the network occurred, tumour microtubes were used for repair. Moreover, the microtube-connected astrocytoma cells, but not those remaining unconnected throughout tumour progression, were protected from cell death inflicted by radiotherapy. The neuronal growth-associated protein 43 was important for microtube formation and function, and drove microtube-dependent tumour cell invasion, proliferation, interconnection, and radioresistance. Oligodendroglial brain tumours were deficient in this mechanism. In summary, astrocytomas can develop functional multicellular network structures. Disconnection of astrocytoma cells by targeting their tumour microtubes emerges as a new principle to reduce the treatment resistance of this disease.